Studies of the altered motor responses to levodopa occurring in advanced Parkinsonian patients revealed that the latency-to-peak motor response correlated closely with symptom duration and severity. The results suggest that compensatory presynaptic mechanisms, especially accelerated dopamine turnover and release, contribute to the absence of Parkinsonian symptoms until most nigrostriatal dopaminergic neurons have degenerated. In a related laboratory investigation, levodopa treatment of Parkinsonian rats with stable destruction of more than 95% of their dopaminergic neurons leads to a progressive shortening in the duration of levodopa's motor effects. This response alteration, resembling the wearing-off phenomena that develop in Parkinsonian patients, did not occur in less severely lesioned rats, suggesting that postsynaptic changes loss of dopamine neurons must exceed a relatively high threshold before levodopa treatment produces changes, evidently at the postsynaptic level, that favor the rapid appearance of wearing-off fluctuations. A subsequent clinical study confirmed that, contrary to long-held beliefs, postjunctional alterations, possibly involving relatively plastic striatal dopaminoceptive systems, also account for most of the shortening in the duration of levodopa action that underlie wearing-off fluctuations in parkinsonian patients. Previous studies by the Section demonstrated the ability of the glutamate system to alter motor responses to dopaminergic stimulation. In addition, we found that repeated levodopa administration down-regulated D1 dopamine receptor mediated responses, up~regulated those mediated by D2 receptors, and progressively reduced the duration of the motor response to levodopa. Acute co-treatment with the noncompetitive NMDA antagonist MK-801 completely reversed all these changes, suggesting that NMDA receptor-mediated mechanisms contribute to the response changes associated with chronic levodopa treatment and that NMDA antagonists act to reverse the motor response complications attending long-term levodopa therapy. Since degeneration of cortical glutamatergic projections is a consistent finding in Alzheimer's disease, we evaluated the possibility that glutamate system stimulation might confer symptomatic benefit. Cycloserine, an indirect agonist at certain (NMDA) glutamate receptors, had no consistent effect on neuropsychological outcome measures, suggesting that short-term potentiation of NMDA-mediated glutamatergic transmission may not prove useful in the symptomatic treatment of this disorder.